Antiviral pharmaceutical preparations and methods for their use

ABSTRACT

The present invention relates to a method and pharmaceutical composition for treating herpes group virus infections in mammals, and in particular, in humans, by administering an effective antiviral amount of lidocaine or a pharmaceutically acceptable salt thereof.

This application is a divisional of Ser. No. 587,398, filed Mar. 8,1984, now U.S. Pat. No. 4,628,063.

FIELD AND BACKGROUND OF THE INVENTION

This invention relates to a method and pharmaceutical composition fortreating herpes group virus infections in mammals, with specificemphasis upon the treatment of herpes simplex virus infections inhumans.

There are four separate herpes group viruses which infect and causedisease in humans. There are (1) herpes simplex virus 1 and 2. (HSV-1and HSV-2); (2) cytomegalovirus (CMV); (3) varicella-zoster virus (VZ)and Epstein-Barr virus (EB). The distinct clinical entities caused byherpes simplex virus (types 1 and 2) are given in Table 1. The clinicalentities caused by cytomegalovirus, varicella-zoster virus, andEpstein-Barr virus are described below.

                  TABLE 1                                                         ______________________________________                                        DISEASE ATTRIBUTABLE TO                                                       HERPES SIMPLEX VIRUS INFECTION                                                ______________________________________                                        Herpes Labialis  Disseminated Herpes                                          Genital Herpes   Occupational Herpes                                          Neonatal Herpes  Herpetic Gingivostomatitis                                   Herpetic Keratitis                                                                             Meningitis (Aseptic)                                         Eczema Herpeticum                                                                              Encephalitis                                                 ______________________________________                                    

Herpes viruses are a large family of viruses which containdeoxyribonucleic acid (DNA) and are surrounded by an envelope. Theyoccur throughout nature and have been found to infect many forms of lifeincluding vertebrates and invertebrates and even fungi. One of theirprimary biological characteristics is to latently exist in an infectedhost after the primary or initial infection and in some instances, causerecurrent disease in that host due state of latency can endure over thelifetime of an individual animal.

The first infection in humans caused by HSV-1 is generally an infectionin childhood in which the virus actively infects the mucous membranes ofthe mouth and oral region. The clinical entity produced by thisinfection is called gingivostomatitis. After the initial infection runsits course, the virus becomes latent in the nerve centers (ganglia)which supply the sensory nerve to the infected area. At any point in thelife of the individual, after the initial infection, due to varioustrigger factors which have commonly been called "stress factors," andwith an unknown mechanism, the virus may reappear and cause infection indifferent parts of the oral or facial skin region and the resultantclinical entity is called "herpes labialis." The common names for thismalady are "cold sores" or "fever blisters."

A second significant and serious disease, most often caused by HSV-2, isgenital herpes (herpes progenitalis) which occurs most often as a directresult of venereal acquisition of HSV-2 from an infected individual.Once HSV-2 initially infects the genital region, it too becomes latentin the individual and can reoccur, giving rise to a series of herpesgenital lesion episodes. As seen in Table 1, there are other clinicalentities caused by HSV-1 and HSV-2 and these are all important in humandisease.

Varicella-zoster (VZ) virus is another virus of the herpes group whichcauses distinct and well-known diseases in man. The first disease causedby VZ virus is chicken-pox (varicella). Generally, chicken-pox is achildhood disease, the virus being acquired through respiratory dropletsspread from an infected individual to an uninfected individual.Chicken-pox is a systemic disease which produces vesicular lesions overthe body of the infected person. Once the disease runs its course, thevirus becomes latent in the nerves of the body and remains in a latentstate throughout the life of the individual.

In some individuals, for unknown reasons, the virus may reoccur later inlife and cause the clinical entity known as shingles (zoster). Shinglescan be a particularly painful disease, and the pain can endure evenafter the lesions of the disease have cleared up (post-zosterneuralgia).

Cytomegaloviruses (CMV) are a group of viruses within the herpes virusfamily which are widespread in humans and numerous other mammals. Agreat majority of human CMV infections are subclinical; that is, theprimary infection occurs with no signs or symptoms. An exception to thisis a congenital infection which occasionally gives rise to cytomegalicinclusion body disease of infants. There is also a mononucleosis-likesyndrome caused by this virus.

A great majority of series cases due to CMV infection come fromrecurring infections in immuno-compromised individuals, such as intransplant patients and in cancer patients. It has been estimated thatsilent CMV infections have occurred in a majority of humans by the timeadulthood is reached.

Epstein-Barr (EB) virus is the causative agent of infectiousmonomucleosis and is another member of the herpes virus family. Thisvirus is unique among the herpes virus group in its ability to replicateonly in certain types of lymphoid cells called B-cell lymphocytes.Infections mononucleosis is a self-limited lymphoproliferative diseasewhich generally has a benign course and only rarely is severe, there is,occasionally, deep organ involvement, such as in the liver and otherpotentially serious complications of this disease. To date, there is noknown effective treatment for EB virus infection.

Some drugs are available for treatment of herpes group virus infectionsof mamals. However, they do not and cannot be used to treat all herpesdiseases.

In general, antiviral drugs fall into discreet categories based upontheir mechanism of action. There are nucleotide analogs which interfereor halt RNA or DNA synthesis. Some compounds have the property ofinhibiting maturation steps in the replication cycle of viruses. Othersinterfere with binding or absorption of viruses to specific hosts cellsor tissues. Still others prevent the uncoating of the viruses followingabsorption into a cell and some restrict the spread of progeny virusesfrom cell to cell or from infected tissues to other sites.

The currently available anti-herpetic agents fall into the nucleic acidinhibition category and generally are purine or pyrimidine analogs. Thefirst of these is IUDR (which is 5'-iodo 2' deoxyuridine). This compoundis a halogenated pyrimidine analog and is taken up into cells,phosphorylated by viral and cellular thymidine kinases, and isincorporated into DNA instead of thymidine. DNA is replicated, but viralmaturation fails because defective proteins are specified by the alteredDNA. This compound is toxic to both uninfected and infected cells and assuch, is less selective than the following agents. IUDR is usedclinically only for herpetic keratitis lesions (eye infections) becauserapid re-epithelialization of the cornea somewhat mitigates itstoxicity.

The second agent somewhat useful for treating herpes infections is Ara-C(1-beta arabinofuranosylcytosine). Ara-C is an analog of cytidine and istaken up by infected and uninfected cells and is incorporated intonascent DNA following phosphorylation by viral and cell phosphorylases.It is less inhibitory to DNA synthesis than is IUDR, but it inhibitsboth DNA polymerase and the nucleotide diphosphate reductases. It istoxic to both infected and uninfected cells and is not used clinicallybecause of this toxicity.

Yet another anti-herpetic compound is Ara-A (9-betaarabinofuranoxyladenine). Ara-A is deaminated to arabinosyl hypoxanthineand is phosphorylated to mono-, di-, and triphosphate derivatives whichact as competitive inhibitors of DNA polymerase. The DNA polymerase thatis specified by the herpes simplex virus is inhibited to a greaterextent than cellullar DNA polymerase and Ara-A is therefore moreselective than IUDR or Ara-C. Ara-A is utilized clinically for thetreatment of herpetic encephalitis.

Acyclovir (9-2-beta hydroxyethomethylguanine) is another anti-herpeticdrug, a guanine analog which is converted to the active triphosphate byherpes specified thymidine kinases in infected cells. It is more readilyphosphorylated in infected than in uninfected cells. The phosphorylatedacylguanine inhibits viral DNA polymerase to a significantly greaterdegree than it does a cellular enzyme and is less toxic because of this.Acyclovir also seems to be less subject to metabolic degradation thanother inhibitors. It is used clinically or primary genital herpessimplex infections and for disseminated herpes infections inimmunocompromised individuals.

Phosphonoacetic acid specifically inhibits viral DNA polymerase but itis too toxic for use in humans. Trisodium phosphoformic acid inhibitsherpes specified DNA polymerase and is less toxic than phosphonoaceticacid, but it is also mutagenic and is not used clinically. Interferon,extracted from human fibroblast lymphocytes or manufactured usingrecombinant DNA techniques is moderately effective in some reports ofits use clinically but scientific studies have demonstrated that itfails to inhibit viral replication directly. Its mechanism of action isattributable to protection of uninfected cells adjacent to infectedcells by an unknown protective action. Interferons are cell specific,not viral specific, in their effects and cause antiviral resistance byactivating cellular genes for antiviral proteins which interact withcell surface. RNA and slow replicating viruses are the best interferoninducers and responders. Herpes simplex is a poor interferon inducer anda poor responder to interferon treatment.

A whole array of other drugs, generally nucleotide inhibitors andanti-metabolites, have been shown to be effective in their antiviralproperties in cell culture and sometimes in animals; however, thesedrugs have not been proved to be efficacious in the treatment of HSVinfections in humans. Because of their cytotoxicity, many of these drugslikely will have highly toxic properties when used to treat humans forherpes infections.

SUMMARY OF THE INVENTION

We have discovered that an amino-amide which is commonly calledlidocaine (2-diethylaminoacetyl-2 6-xylidide) is an effective antiviralagent in cell culture against HSV-1 and HSV-2 and is able to treatherpes virus infections of mammals. It is particularly effective in thetreatment of HSV oral and genital lesions of humans.

Furthermore, we have discovered that the addition of pantothenic acid orits alcohol and salt forms, dexpanthenol and pantothenate respectively,to lidocaine or lidocaine hydrochloride significantly enhances theantiviral activity of those drugs.

Accordingly, this invention broadly concerns a method for treatingherpes group virus infections in mammals which comprises administeringto the mammal an effective antiviral amount of lidocaine or apharmaceutically acceptable salt thereof. In a further aspect, thisinvention provides a method of treating herpes group virus infections inhumans by administering, either in topical or parenteral form, aneffective antiviral amount of lidocaine or a pharmaceutically acceptablesalt thereof in combination with pantothenic acid or its alcohol andsalt forms.

In a still further aspect, this invention provides a pharmaceuticalcomposition for the treatment of herpes group virus infections inmammals which comprises a combination of lidocaine or a pharmaceuticallyacceptable salt thereof, with pantothenic acid or its alcohol and saltforms.

Lidocaine was the first amino-amide to demonstrate clinical usefulnessas a local anesthetic and many topical anesthetics that have beensynthesized since the introduction of lidocaine are also amino-amides.The following compounds which are chemically related to lidocaine havebeen introduced into clinical practice in recent years. Prilocaine(2-propylamino-2'-propionotoluidine) (Lofgren N, Tegner C: Acta ChemScand 14:486, 1960); Etidocaine(2-N-ethylpropylamino-2',6'-butyroxylide) (Adams H J, Kronberg G H,Takman B H: J Pharmacol Sci 61:1829, 1972); Mepivacaine (1-methyl-2',6'hexahydropicolinylxyledide) (Ulfendahl H R: Acta Anaesthesiol Scand1:81, 1957); and a homologue of Mepivacaine which is called Bupivicaine(1-butyl-2',6'-hexahydropicolinylxyledide) (Henn F, Brattsand R: ActaAnaesthesiol Scand, (Suppl) 21, p. 9, 1966).

To the extent that these and other chemically related syntheticamido-amines may function in the same manner as lidocaine and exhibitantiviral activity against herpes group viruses, such compounds are tobe considered as the equivalent of lidocaine for purposes of the presentinvention and within the scope of the appended claims.

Chemically, lidocaine is diethylaminoacet-2,6-xylidide and has also beendesignated as xylocaine or lignocaine. Lidocaine has a small excitationvalue and a pKa value of 7.855. These are important properties in thepharmacodynamics of lidocaine. The chemical crystallizes as a fine whiteneedle which melts between 66-69 centigrade. It is soluble in alcohol,chloroform, oils, benzene ether, and ethyl acetate. It is only slightlysoluble in water. The hydrochloride salt is highly soluble in water andmelts at 128°-130° C. Solutions of lidocaine are stable and withstandboiling or autoclaving with strong acids or alkali for several hours.This is an extraordinary stability. Normally, solutions of lidocainehydrochloride have a pH value of 6.7 to 6.9. Lidocaine is chemicallystable in the laboratory; however, it can easily be biodegraded in vivoby the liver and in vitro by liver slices (Sung, C. Y. and Truant, A. P.1954 J. Pharmacol. and Exper. Therap. 112, 432). The principal use oflidocaine in medicine has been as a local anesthetic or as an agent forperipheral nerve blocks or central nerve blocks or spinal anesthesia. Ithas also been used as an anti-arrhythmic. Its chemistry, clinicalaspects, pharmacokinetic aspects, general pharmacological andtoxological aspects have all been described and are a record of state ofthe art (Covino, B. G. Vassalo, H. G. The Scientific Basis of ClinicalAnesthesia. Publ: Grune & Stratton, New York, N.Y. 1976).

Schmidt et al. (Experentia V. 273, pp 261-262) have shown that lidocaineis able to inhibit DNA synthesis in cell cultures, and that thisinhibition is probably a result of the complexing of lidocaine withmembranous structures in the cells which thereby interferes with thesite of DNA synthesis. VorHees et al. (U.S. Pat. No. 4,181,725) haveshown that lidocaine can be used in an ointment in a topical treatmentof humans for proliferative skin diseases such as psoriasis.

Until our discovery described herein, however, lidocaine has never beendescribed as having antiviral effect, either in cell cultures, animals,or in human beings.

Pantothenic acid, and its alcohol and salt forms, dexpanthenol andpantothenate respectively, are generally known for their vitaminactivity. Pantothenic acid is commonly referred to as vitamin B5. Untilour discovery, these compounds have never been described as havingantiviral effect either in cell cultures, animals, or in human beings.

When lidocaine is administered in the form of a pharmaceuticallyacceptable salt, the salt will be a non-toxic salt, suitably an acidaddition salt. An example of a pharmaceutically acceptable salt oflidocaine is lidocaine hydrochloride.

While it is possible for lidocaine or its pharmaceutically acceptablesalt to be administered as the raw material, it is preferablyadministered in the form of a pharmaceutical formulation. Thepharmaceutical formulation will comprise the active compound, togetherwith a pharmaceutically acceptable carrier therefor. The carrier must be"acceptable" in the sense of being compatable with the other ingredientsof the formulation and not deleterious to the recipient thereof. Thepharmaceutical formulations may be prepared in any of the methods wellknown in the art of pharmacy.

When the pharmaceutical formulation is applied topically, the carriermay suitably comprise a solution, ointment or gel base. The base, forexample, may comprise one or more of the following: petrolatum, lanolin,polyethylene glycols, bee wax, mineral oil, diluents such as water andalcohol, and emulsifiers and stabilizers. Topical formulations maycontain a concentration of the lidocaine or lidocaine salt from about0.1 to about 10% w/v (by weight per unit volume). Pharmaceuticalformulations suitable for parenteral administration includes sterilesolutions or suspensions of the active compound in water or othersuitable vehicle.

Lidocaine and its pharmaceutically active salts have been found toexhibit antiviral activity in cell culture and animal model systems at aconcentration ranging from 0.5 mg/ml (0.05%) to 100 mg/ml (10%). Therecommended intramuscular daily dosage in humans in 4.3 mg/kg. of bodyweight or 2.0 mg per pound of body weight. Thus, in a 150 pound man (70kg.), the recommended daily dosage is 300 mg. This generally is injectedin a single intramuscular bolus form. In topical (ointment or solution)form, a representative dosage would be the application of a 0.5 to 10%topical application (most desirably 0.5 to 4%) 3 to 4 times daily. Whenpantothenic acid or dexpanthenol is included in the formulation, it ispreferably present at a concentration of from 5-50 mg/ml.

BRIEF DESCRIPTION OF THE DRAWINGS

These and other features and aspects of this invention will becomeapparent from the following specifications, and from the accompanyingdrawings in which

FIGS. 1-9 are graphs which illustrate the effectiveness of the presentinvention against HSV-1 virus.

IDENTIFICATION OF LIDOCAINE AS AN ANTIVIRAL SUBSTANCE

A. Cell Culture

The following experiments were specifically designed to determine iflidocaine hydrochloride possesses antiviral activity against thereplication of herpes simplex virus type 1 in Vero cell cultures.Harvest experiments were done in which HSV-1 infected cell cultures werepost-treated with lidocaine hydrochloride at a number of concentrations.The vessels containing the cells were harvested when the cytopathiceffect (CPE) in the untreated virus (negative) control cultures was 3⁺to 4⁺ (approximately 90% of cells showing CPE). The positive control inthese experiments was IUDR. The viral harvest were then plaque assayedon vero cells to determine the number of plaque forming units permillimeter (pfu/ml) produced in each test flask as compared to thecontrols. Table 2 shows the results of these harvest titrations andclearly points out that lidocaine hydrochloride is able to prevent thereplication of herpes simplex virus type 1 in cell culture, thereforeestablishing it as antiviral agent. Table 2 gives the results of variousconcentrations of lidocaine hydrochloride from 0.4 to 1.8 mg/ml.Significant antiviral activity is seen throughout this range ofconcentrations. At a concentration of 2.0 mg/ml, lidocaine hydrochloridewas toxic in cell cultures. FIG. 1 shows the results of decreasingconcentrations of lidocaine hydrochloride, and the results shownindicate the antiviral activity of lidocaine hydrochloride issignificant down to 0.1 mg/ml.

                                      TABLE 2                                     __________________________________________________________________________    DOSE-RESPONSE OF LIDOCAINE-HCL VERSUS HSV-1 (MOI-1.0)                                             HARVEST                                                                             LOGS LOG                                            COMPONENT                                                                             *CONCENTRATION                                                                            PFU/ML                                                                              VIRUS                                                                              REDUCTION                                      __________________________________________________________________________    Virus Control                                                                         --          1.4 × 10.sup.6                                                                6.2  --                                             Idoxuridine                                                                            10 ug/ml   7.5 × 10.sup.3                                                                3.9  2.3                                            Lidocaine HCL                                                                         1.8 mg/ml   0     0    >3.0                                           Lidocaine HCL                                                                         1.6 mg/ml   0     0    >3.0                                           Lidocaine HCL                                                                         1.4 mg/ml   0     0    >3.0                                           Lidocaine HCL                                                                         1.2 mg/ml   0     0    >3.0                                           Lidocaine HCL                                                                         1.0 mg/ml   0     0    >3.0                                           Lidocaine HCL                                                                         *0.8 mg/ml  4.5 × 10.sup.3                                                                3.7  2.5                                            Lidocaine HCL                                                                         0.4 mg/ml   3.7 × 10.sup.4                                                                4.6  1.6                                            __________________________________________________________________________

Because the herpes simplex virus replication cycle occurs in awell-described, orderly temporal fashion, one approach to estimating thestage of replication blocked by lidocaine hydrochloride is to perform aseries of post-infection treatments with the agent, in a one-stepreplication cycle. In this experiment, viral cell cultures were infectedwith HSV-1 at a multiplicity of 3 and allowed to adsorb for one hour.The inoculum was then removed, and duplicate infected cultures were thentreated at 1, 2, 4, 6, 8, 10, 12, 14 and 16 post-infection with 1.8mg/ml of lidocaine hydrochloride in maintenance medium. At 18 hours, allcultures were washed three times with phosphate buffered saline. Onemilliliter of phosphate buffered saline was added back to the monolayer,and the cultures were then harvested by three cycles of freeze-thawingfollowed by centrifugation. The viral harvest was then titrated on viralcells, and the pfu/ml of harvest virus was calculated. The control inthis experiment was a one-step multiplication cycle of untreated viralcells also infected but harvested at the same time as the treatedcultures. FIG. 2 was generated from these results. From these results,it is apparent that treatment of HSV-1 infected cells with 1.8 mg/ml oflidocaine as late as 12 hours after infection is able to causesignificant reduction (48%) in virus replication. When treated up to 8hours post-infection, over 95% of virus production was inhibited. Evenat 10 hours post-infection, 84% of virus production was inhibited.Because of this unusual effect, it is possible that lidocaine may actsomewhat late in the herpes replication cycle unlike many effectiveherpes simplex antiviral drugs such as the nucleotide analogs previouslydescribed.

When dexpanthenol, in concentrations ranging from 0.6 mg/ml to 9.6mg/ml, was tested against herpes simplex virus Type 1 in cell cultureusing the same assay system as described for lidocaine hydrochloride, amarked antiviral activity was seen for concentrations of dexpanthenolabove 1.2 mg/ml. FIG. 3 gives the results of these experiments. In FIG.3, it is significant that 9.6 mg/ml of dexpanthenol shows a reduction inviral titer of greater than 99.99% of the original amount of virus.Furthermore, in separate experiments, when 0.4 mg/ml of lidocaine wasmixed with 0.8 mg/ml of dexpanthenol, a reduction in virus titer 50%greater than that seen with lidocaine or dexpanthenol at the sameconcentrations alone was observed.

These results have adequately demonstrated that lidocaine hydrochlorideand dexpanthenol are effective as antiviral agents in cell culture andact by inhibiting the replication of herpes simplex virus in cellcultures.

Additional studies carried out indicate that lidocaine hydrochloride incombination with dexpanthenol in either topical or parenteral forms iseffective in reducing the severity of developing herpes simplex Type 1lesions in a hairless mouse model system when given at the time ofinfection of the mice or when treatment is continued for one week afterinfection. It is also effective in reducing the severity of developingHSV-1 lesions in hairless mice when injected at the time of initialonset of the lesions. The results of these experiments are reportedbelow.

B. Animal Experiments

EXPERIMENT ONE

In this experiment, animals were scratch inoculated with HSV-1 andplacebo (Group 1) or lidocaine hydrochloride-dexpanthenol (Group 2)ointment (lidocaine 40 mg/ml para amino-benzoic acid 5%, panthenol 50mg/ml in a base of wheat germ oil, cetyl alcohol, petrolatum, stearylalcohol, tween 80, water, succinic acid, and ascorbic acid added aspreservative and anti-oxidant) was applied ten minutes later and oneadditional time on the first day. The animals were then treated dailyfor seven days. FIG. 4 shows the results of the responder mean lesionscores for the placebo and the treated animals. The responder meanlesion scores are defined as the cumulative lesion score of thoseanimals which actually had lesions divided by the total number ofanimals with lesions. In this and every following figure, the control(placebo group) is indicated by squares and the treatment group isindicated by diamond shaped symbols. The arithmetical difference betweenthe treatment and the control group is indicated by triangles. Theresults of this experiment indicate there is a significant difference(P<0.005) between the control animals and the prophylactically treatedanimals. Lidocaine hydrochloride-dexpanthenol ointment applied dailyafter the time of scratch inoculation prevents the development oflesions as severe as those in the control group to a significant degree.This effect is seen for the first ten days of lesion development andhealing. The scores even out after approximately ten days. FIG. 5compares the same groups of animals with respect to the total meanlesion scores. Total mean lesion score is defined as the total lesionscore of animals with lesions divided by the total number of animals.This system of analysis takes into account those animals which did notdevelop lesions. In FIG. 5, it is seen that there is a significantdifference between the treated animals and the control group atapproximately the same level as seen in FIG. 4. The level ofsignificance is P<0.005. This indicates that the two methods of dataevaluation do not produce a difference in the outcome. FIG. 6 comparesthe total number of animals which developed lesions in the placebo andtreatment groups and indicates that there was not a significantdifference in the number of animals which developed lesions. Theseresults indicate in this experiment that lidocainehydrochloride-dexpanthenol ointment when applied at the time of scratchinoculation with herpes simplex virus Type 1 in hairless mice reducesthe severity of developing lesions to a statistically significantdegree.

EXPERIMENT TWO

In this experiment, the animals were scratch inoculated with HSV-1 andcutaneous lesions were allowed to develop. The results are given inFIGS. 7 through 9. At the time of the first appearance of lesions,lidocaine hydrochloride-dexpanthenol solution was injectedintramuscularly into the animals one time daily for one week.(Concentration of lidocaine hydrochloride per injection was 20 mg/ml;concentration of dexpanthenol was 30 mg/ml.) Approximately 0.1milliliter was injected. The purpose of this group was to see ifsystemic lidocaine hydrochloride in combination with dexpanthenol couldbe used to successfully treat cutaneous HSV-1 lesions in the infectedhairless mice after onset of the lesions. A placebo injectable solutionwas used as a control.

FIG. 7 indicates that there is a significant difference between thecontrol and treated groups in the responder mean lesions score analysis(P<0.001).

FIG. 8 similarly indicates that a difference in the total mean lesionscore between the placebo and the control group.

FIG. 9 indicates that the treatment group contains somewhat feweranimals that developed lesions than a control group. This is aninsignificant finding since treatment was begun after lesions developed.These results indicate that injectable form lidocainehydrochloride-dexpanthenol mixture is effective in reducing the severityof herpes simplex Type 1 induced lesions in hairless mice when given atthe time the first lesions initially appear in the animals.

These results indicate in a scientifically determined manner that thecombination of lidocaine hydrochloride and dexpanthenol, topicallyapplied or injected, is able to successfully treat herpes simplex virusinfections in mammals.

C. Human Case Studies

EXAMPLE 1 Male Herpes Genitalis

This study comprised 14 cases, ranging in age from 16 to 50. Allpatients affected had had previous recurrent herpes of the genitals,with episodes recurring over periods of 1 to 6 months. The duration ofgenital episodes was between 10 to 14 days with intense burning beforethe appearance of blisters, followed by painful blisters before andafter breaking, formation of scab, and remission. In this study,patients were seen before and 1 to 2 days after the appearance ofblisters. They were advised to rub the affected area gently with a smallamount of lidocaine hydrochloride-dexpanthenol in a specially preparedointment base 3 times a day in the morning, afternoon, and before goingto bed. They were strongly advised against any sexual activity.

RESULTS

The pre-blister itching and pain associated with the blisters wasmarkedly reduced or disappeared 15 to 20 minutes after the firstapplication. In 6 out of 14 patients, itching and/or pain reappeared 2to 3 hours after the first application, but symptoms were to a lesserintensity. After the second application, 8 to 10 hours later, itching,discomfort, and pain disappeared completely and did not reappear untilthe complete remission of the lesions. While the disappearance of thesubject's symptoms--itching, discomfort, and pain--was expected due tothe anesthetic effect of lidocaine, the unexpected and beneficialresults obtained were the disappearance of blisters in 2 to 3 days,together with the disappearance of symptoms of local inflammation anddiscomfort. All cases treated showed a definite abortion or shorteningof the 7 to 10 day itching, blister, scab cycle. They all cleared upafter 2 to 3 days' application of lidocaine hydrochloride ointment,regardless of the time when the treatment was instituted.

EXAMPLE 2 Anal Herpes

One patient experiencing recurrent anal herpes was treated. The patientshowed definite improvement after 6 days with diminished pain. After 12days, 75% improvement in pain and disappearance of eruptions. Previousanal herpetic episodes were lasting between 14 to 30 days withconsiderable pain and discomfort.

EXAMPLE 3 Herpes Zoster

Two patients with herpes zoster were treated. One patient experiencedincreased pain during a 24-hour period, and the treatment wasdiscontinued after one day. The other patient with herpes zoster of thehead showed definite improvement after the first treatment andconsistently improved thereafter with marked lessening of pain anderuptions.

EXAMPLE 4 Herpes of the Hand

One patient was treated. Complete remission in 2 days.

EXAMPLE 5 Herpes of the Face and Oral Regions (Herpes Labialis)

Five patients were treated. Complete remission in 2 to 5 days anddiminishing of pains and symptoms of the episode.

EXAMPLE 6 Additional Case Reports 25-Year Old Male with Genital HerpesLesions

The site of the lesion was the shaft of the penis. There was stingingand a prickly feeling at the site of the lesion; mild itching, and noburning; with a history of recurrent (6 to 7 previous episodes) lesions.This patient was treated with a combination of lidocainehydrochloride-dexpanthenol mixture in ointment form and injectable form.The lesions were healed completely in 3 days with no pain and verylittle discomfort, and there was no new blister formation.

26-Year Old Male

The site of the lesion was the dorsal area of the penis. Very mildlesions. There was a sensation of slight burning. Patient has had herpesepisodes for 3-4 years and several episodes of gonorrhea. Thisindividual was treated with a combination of ointment at the site of thelesions and injectable lidocaine. The lesions disappeared in 3 days. Nonew blisters were formed, and the pain disappeared.

34-Year Old Female

The site of the lesion was the lip, lower right side; very smallblisters. This patient was presented at 5 days into the episode; noprior episodes; and no history of venereal infections. The treatment wassuccessful and complete remission occurred in 3 days.

23-Year Old Female

Lesions just inside of the vaginal orifice. There were burning anditching sensations. These were extremely tense lesions. No history ofprior episodes; no history of venereal infections. Presented withlesions of duration of about 5 days. Had tried several other presumedantiviral compounds with poor results. Upon treatment with lidocaineHCl-dexpanthenol ointment, in injectable form, the burning, pain andlesions disappeared within 4 days.

55-Year Old Female

Herpes lesions on the left hand at the base of the third and fourthfingers; red, swollen, broken blisters, oozing, with deep laceration atthe base of the index finger. There was a drawing pain in the hand,itching, and burning, with pain in axillary region. The patientpreviously had vesicular lesions on the lips for 10 days, whichdisappeared. The lesions on the hand appeared following lip involvement.The lesions on the hand had been there 1 week prior to treatment.Patient had a temperature of 101° on the day prior to the visit. On the3rd day after treatment was commenced with lidocainehydrochloride-dexpanthenol ointment, and injectable form, the pain andswelling had subsided. All lesions disappeared within 2 weeks.

45-Year Old Female

Lesions on the introitus of the vagina; irritated, painful. This was achronic condition, and the patient had been uncomfortable for 5 to 6months. Treatment was commenced with lidocainehydrochloride-dexpanthenol ointment, and injectable form, and thelesions disappeared within 3 days after a commencement of treatment.

That which is claimed is:
 1. A method of treating herpes group virusinfections in a mammal which comprises administering to said mammal aneffective antiviral amount of a mixture comprising:(a) lidocaine or apharmaceutically acceptable salt thereof in a concentration of 0.1 to10% w/v, and (b) pantothenic acid or a pharmaceutically acceptable saltthereof in a concentration of 5 to 50 mg/ml.
 2. A method as in claim 1in which the lidocaine is administered in the form of the hydrochloridesalt thereof.
 3. A method of treating cutaneous herpes simplex virusinfections in humans which comprises topically applying to the infectedareas of the human an ointment or gel containing an effective antiviralamount of a mixture comprising:(a) lidocaine or a pharmaceuticallyacceptable salt thereof in a concentration of 0.1 to 10% w/v, and (b)pantothenic acid or a pharmaceutically acceptable salt thereof in aconcentration of at least 5 to 50 mg/ml.
 4. A method according to claim3, which comprises administering the lidocaine or lidocaine salt at adaily dosage rate of about 2.0 mg. per pound of body weight.
 5. A methodof treating herpes zoster in humans which comprises parenterallyadministering to the human a mixture:(a) lidocaine or a pharmaceuticallyacceptable salt thereof in a concentration of 0.1 to 10% w/v, and (b)pantothenic acid or a pharmaceutically acceptable salt thereof in aconcentration of 5 to 50 mg/ml.
 6. A method according to claim 5, whichcomprises administering the lidocaine or lidocaine salt at a dailydosage rate of about 2.0 mg. per pound of body weight.
 7. Apharmaceutical composition for the treatment of herpes group virusinfections in mammals which comprises an effective antiviral amount of amixture of:(a) lidocaine or a pharmaceutically acceptable salt thereofin a concentration of 0.1 to 10% w/v, and (b) pantothenic acid or apharmaceutically acceptable salt thereof in a concentration of 5 to 50mg/ml.
 8. A pharmaceutical composition according to claim 7 in apharmaceutically acceptable ointment base.
 9. A pharmaceuticalcomposition according to claim 7 comprising the mixture in a sterilesolution.
 10. A pharmaceutical composition as in claim 7 wherein thelidocaine is administered in the form of the hydrochloride salt thereof.